Trimethoprim is widely distributed in the body, with some intracellular sequestration, which results in an apparent volume of distribution greater than that of the body water. Sulphonamides, on the other hand, are more confmed to the blood and extracellular fluid. In most body fluids and secretions the concentration ratio of trimethoprim/sulphonamide is also usually less than in the blood, typically 1:2 to I :5, although there are wide individual variations. Since sulphonamides alone are not active at low concentrations and a ratio with a low sulphonamide content is unsatisfactory for synergy against the majority of bacteria, even in antagonist-free media, the exact role of sulphonamides in therapy with cotrimoxazole is still open to debate.